FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion Injury
Dendritic cells (DCs) are central in regulating immune responses of kidney ischemia-reperfusion injury (IRI), and strategies to alter DC function may provide new therapeutic opportunities. Sphingosine 1-phosphate (S1P) modulates immunity through binding to its receptors (S1P1-5), and protection from...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01278/full |
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| author | Thomas V. Rousselle Canan Kuscu Cem Kuscu Kailo Schlegel LiPing Huang Maria Namwanje James D. Eason Liza Makowski Daniel Maluf Valeria Mas Amandeep Bajwa |
| author_facet | Thomas V. Rousselle Canan Kuscu Cem Kuscu Kailo Schlegel LiPing Huang Maria Namwanje James D. Eason Liza Makowski Daniel Maluf Valeria Mas Amandeep Bajwa |
| author_sort | Thomas V. Rousselle |
| collection | DOAJ |
| description | Dendritic cells (DCs) are central in regulating immune responses of kidney ischemia-reperfusion injury (IRI), and strategies to alter DC function may provide new therapeutic opportunities. Sphingosine 1-phosphate (S1P) modulates immunity through binding to its receptors (S1P1-5), and protection from kidney IRI occurs in mice treated with S1PR agonist, FTY720 (FTY). We tested if ex vivo propagation of DCs with FTY could be used as cellular therapy to limit the off-target effects associated with systemic FTY administration in kidney IRI. DCs have the ability of regulate innate and adaptive responses and we posited that treatment of DC with FTY may underlie improvements in kidney IRI. Herein, it was observed that treatment of bone marrow derived dendritic cells (BMDCs) with FTY induced mitochondrial biogenesis, FTY-treated BMDCs (FTY-DCs) showed significantly higher oxygen consumption rate and ATP production compared to vehicle treated BMDCs (Veh-DCs). Adoptive transfer of FTY-DCs to mice 24 h before or 4 h after IRI significantly protected the kidneys from injury compared to mice treated with Veh-DCs. Additionally, allogeneic adoptive transfer of C57BL/6J FTY-DCs into BALB/c mice equally protected the kidneys from IRI. FTY-DCs propagated from S1pr1-deficient DCs derived from CD11cCreS1pr1fl/fl mice as well as blunting mitochondrial oxidation in wildtype (WT) FTY-DCs prior to transfer abrogated the protection observed by FTY-DCs. We queried if DC mitochondrial content alters kidney responses after IRI, a novel but little studied phenomenon shown to be integral to regulation of the immune response. Transfer of mitochondria rich FTY-DCs protects kidneys from IRI as transferred FTY-DCs donated their mitochondria to recipient splenocytes (i.e., macrophages) and prior splenectomy abrogated this protection. Adoptive transfer of FTY-DCs either prior to or after ischemic injury protects kidneys from IRI demonstrating a potent role for donor DC-mitochondria in FTY's efficacy. This is the first evidence, to our knowledge, that DCs have the potential to protect against kidney injury by donating mitochondria to splenic macrophages to alter their bioenergetics thus making them anti-inflammatory. In conclusion, the results support that ex vivo FTY720-induction of the regulatory DC phenotype could have therapeutic relevance that can be preventively infused to reduce acute kidney injury. |
| first_indexed | 2024-12-23T04:02:38Z |
| format | Article |
| id | doaj.art-e1a321347247487bb554ae50d64b3edd |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T04:02:38Z |
| publishDate | 2020-06-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-e1a321347247487bb554ae50d64b3edd2022-12-21T18:00:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-06-011110.3389/fimmu.2020.01278522860FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion InjuryThomas V. Rousselle0Canan Kuscu1Cem Kuscu2Kailo Schlegel3LiPing Huang4Maria Namwanje5James D. Eason6Liza Makowski7Daniel Maluf8Valeria Mas9Amandeep Bajwa10Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United StatesTransplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United StatesTransplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United StatesDivision of Nephrology and the Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, United StatesDivision of Nephrology and the Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, United StatesDepartment of Pediatrics and Genetics, University of Tennessee Health Science Center, Memphis, TN, United StatesTransplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United StatesDepartment of Medicine - Division of Hematology and Oncology, College of Medicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, TN, United StatesTransplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United StatesTransplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United StatesTransplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United StatesDendritic cells (DCs) are central in regulating immune responses of kidney ischemia-reperfusion injury (IRI), and strategies to alter DC function may provide new therapeutic opportunities. Sphingosine 1-phosphate (S1P) modulates immunity through binding to its receptors (S1P1-5), and protection from kidney IRI occurs in mice treated with S1PR agonist, FTY720 (FTY). We tested if ex vivo propagation of DCs with FTY could be used as cellular therapy to limit the off-target effects associated with systemic FTY administration in kidney IRI. DCs have the ability of regulate innate and adaptive responses and we posited that treatment of DC with FTY may underlie improvements in kidney IRI. Herein, it was observed that treatment of bone marrow derived dendritic cells (BMDCs) with FTY induced mitochondrial biogenesis, FTY-treated BMDCs (FTY-DCs) showed significantly higher oxygen consumption rate and ATP production compared to vehicle treated BMDCs (Veh-DCs). Adoptive transfer of FTY-DCs to mice 24 h before or 4 h after IRI significantly protected the kidneys from injury compared to mice treated with Veh-DCs. Additionally, allogeneic adoptive transfer of C57BL/6J FTY-DCs into BALB/c mice equally protected the kidneys from IRI. FTY-DCs propagated from S1pr1-deficient DCs derived from CD11cCreS1pr1fl/fl mice as well as blunting mitochondrial oxidation in wildtype (WT) FTY-DCs prior to transfer abrogated the protection observed by FTY-DCs. We queried if DC mitochondrial content alters kidney responses after IRI, a novel but little studied phenomenon shown to be integral to regulation of the immune response. Transfer of mitochondria rich FTY-DCs protects kidneys from IRI as transferred FTY-DCs donated their mitochondria to recipient splenocytes (i.e., macrophages) and prior splenectomy abrogated this protection. Adoptive transfer of FTY-DCs either prior to or after ischemic injury protects kidneys from IRI demonstrating a potent role for donor DC-mitochondria in FTY's efficacy. This is the first evidence, to our knowledge, that DCs have the potential to protect against kidney injury by donating mitochondria to splenic macrophages to alter their bioenergetics thus making them anti-inflammatory. In conclusion, the results support that ex vivo FTY720-induction of the regulatory DC phenotype could have therapeutic relevance that can be preventively infused to reduce acute kidney injury.https://www.frontiersin.org/article/10.3389/fimmu.2020.01278/fulldendritic cellFTY720mitochondriasphingosine-1-phosphate receptormacrophagesmetabolism |
| spellingShingle | Thomas V. Rousselle Canan Kuscu Cem Kuscu Kailo Schlegel LiPing Huang Maria Namwanje James D. Eason Liza Makowski Daniel Maluf Valeria Mas Amandeep Bajwa FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion Injury Frontiers in Immunology dendritic cell FTY720 mitochondria sphingosine-1-phosphate receptor macrophages metabolism |
| title | FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion Injury |
| title_full | FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion Injury |
| title_fullStr | FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion Injury |
| title_full_unstemmed | FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion Injury |
| title_short | FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion Injury |
| title_sort | fty720 regulates mitochondria biogenesis in dendritic cells to prevent kidney ischemic reperfusion injury |
| topic | dendritic cell FTY720 mitochondria sphingosine-1-phosphate receptor macrophages metabolism |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01278/full |
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